The Section on Directed Gene Delivery assesses the ability of retroviral vectors to deliver efficiently deliver genes to appropriate target cells with the end goal of transferring therapeutic genes to cells of the central nervous system. Our section has developed vectors based on gibbon ape leukemia virus. Vectors bearing GALV envelopes are produced in PG13 cells. These vectors have advantages over MLV vectors in primates and therefore have been extensively used in the therapy of cancers and genetic disorders. Over the course of last year the Section has made improvements to the design of viral vectors used for therapeutic gene delivery to patients and has identified factors critical to infection of human cells by both therapeutic viral vectors based on retroviruses and the wild type retroviral pathogens themselves. It has been a widely held belief that gammaretroviral vectors, in contrast to lentiviral vectors, are restricted in their ability to transduce growth-arrested cells, yet the block to this restriction has not been clearly defined. We have compiled findings regarding the ability of gammaretoviral vectors and replicating gammaretroviruses that express green fluorescent protein as an indicator of infection to infect non-dividing target cells. Specifically we infected fully differentiated PC12 cells (growth arrested in G1 of the cell cycle determined using a red fluorescent G1 indicator gene) transfected with a gammaretrovirus expressing Bcl-xL thus rescuing these cells from cell death induced by differentiating growth factor (NGF) withdrawal. We also showed that our vectors can infect primary cortical neurons indicating that there is no block to infection/transduction even in primary post-mitotic cells permanently arrested in Go rather than G1. These findings suggest that the host range of gammaretroviruses includes post-mitotic and other growth-arrested cells in mammals, and have implications for re-deployment of gammaretroviral gene therapy to neurological disease. We have also examined why some patients treated with gammaretroviral vectors in which the viral promoter is inactivated develop cancers as a consequence of the vector activating an adjacent oncogene. This represents a conundrum since activation of the oncogene appears to occur even the employed vector is self-inactivated for promoter function. We constructed a series of self inactivated (SIN) vectors representative of the currently employed vectors, but lacking an internal promoter. Green fluorescent protein (GFP) was used as a reporter gene. Target cells exposed to these vectors were evaluated for number of integrants and GFP expression at the mRNA level and protein level. We found that viral promoter activity in the vector is not attenuated. These results suggest that the influence of strong residual promoter activity should be taken into consideration when interpreting experimental results obtained using SIN vectors in gene therapy research and only SIN vectors that contain the removal of a larger segment of the viral promoter be used in clinical gene therapy trials. Further systematic modification of gammaretroviral vectors to target astrocytic, neuronal and microglial compartments of the human brain is a current goal of our laboratory.